Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer, and metastasis is the major cause of death in patients with IBC. To date, there are no FDA-approved targeted therapies that are specific for patients with IBC, and the molecular mechanism underlying IBC?s aggressiveness is not well understood. The long-term goal of the applicant?s group is to decrease the mortality associated with IBC by developing a novel therapy. The overall objectives of this application are to determine how the EGFR pathway promotes the progression of IBC and, through understanding the pathway, to identify novel therapeutic targets that could enhance the efficacy of EGFR targeted therapy. The central hypothesis is that the EGFR pathway is highly exploitable as a therapeutic target in IBC because this pathway promotes inflammation and cancer stem-like cell (CSC) self-renewal. The rationale for the proposed research is that identifying and validating novel targets will lead to the development of an efficacious combination-therapy approach to prolonging the survival of patients with IBC. On the basis of strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Determine how the EGFR/COX-2 signaling axis regulates the CSC population in IBC cells; and 2) Determine predictive biomarkers of response to EGFR targeted therapy in patients with IBC. In the first aim, the effect of EGFR/COX-2 activation or inhibition on the IBC CSC population through the mediation of Nodal/TGF? signaling and the involved mechanism will be investigated. Further, potential combination approaches that could enhance the efficacy of EGFR targeted therapy will be identified. In the second aim, the role of EGFR/COX-2/TGF? axis molecules in predicting the response to PmAb will be determined, and the impact of PmAb on regulating the cross-talk between tumor cells and the adjacent microenvironment will be investigated. In addition, for patients receiving EGFR targeted therapy, RNA sequencing of before- and after-treatment samples will be performed to compare the differential gene expression profiles between patients who achieve pathological complete response and those who do not. The proposed research is innovative because it focuses on the unique molecular features of IBC and uses a novel approach of targeting CSC in IBC through EGFR and/or inflammatory-related pathways; also, it utilizes a novel multiplexed immunostaining imaging technology that allows multiple sets of markers to be visualized within the same cells or tissue section. The proposed research is significant because it is expected to fundamentally advance the understanding of IBC and facilitate the development of a novel personalized therapy, leading to much more effective clinical trials for IBC and ultimately, reduced mortality from IBC. The regimen established from this work will also be adopted in a clinical trial for chemoresistant primary non-inflammatory breast cancers with triple-negative receptors, thus extending the clinical impact of this work for breast cancer patients.